Marrow Stromal Cells (MSCs) are a stem cell population resident in the bone marrow that we have recently differentiated into neurons. MSCs may therefore prove useful in the treatment of neurological diseases such as Parkinson's Disease and Alzheimer's Disease through transplantation, and may help define developmental mechanisms. We hypothesize that MSCs differentiate into neurons independent of mitosis, and that Nerve Growth Factor plays a critical role in the process. Our long-term goal is to understand the interplay between MSCs and neural cells derived from the brain. We plan to investigate the relationship between proliferation and differentiation of MSCs, and the influence of neural signals on these events. Specifically, we will 1) define the processes of proliferation and differentiation in MSCs, 2) examine the influences of neurotrophins and their receptors of MSC proliferation and differentiation, 3) delineate the effects of exposure to neural cells on MSC neuronal maturation in culture, and 4) assess the response of MSCs to the complex environment of the developing brain. Molecular analysis of gene expression, intracellular signaling cascades, and sub-cellular distribution of neuronal gone products will delineate the influences of neural signals on MSC proliferation, differentiation and maturation in vitro. Survival, migration, integration and differentiation of MSCs transplanted into the developing brain will characterize the level of plasticity inherent in MSCs. The consequences of MSC exposure to neural signals may provide insight into the feasibility of MSC transplantation in the treatment of neurological disease.